To ensure faithful genome maintenance, chromatids have to be properly segregated to daughter cells. This requires the removal of all physical connections between sister chromatids before cells divide. Besides cohesins, which act as proteinaceous glue, a variety of other chromatid connections have to be equally removed. These include intermediates of DNA recombination such as Holliday Junctions, points at which recombined chromatids have become intertwined, and loci that have not replicated by the time cells reach the metaphase-anaphase transition. Cytologically, the connections between anaphase chromatids can take the form of chromatinized or ultrafine DNA bridges and such connections are frequently found in dividing cells, even when not treated with DNA damaging agents. Failure to process chromatin bridges impedes the segregation of chromatids and leads to genome instability, aneuploidy, and polyploidization.
Over the last years, it has been recognized that several redundant mechanisms resolve connections between chromatids before cell division. This includes a complex composed of the BLM helicase, topoisomerase III and RMI1, the structure-specific nuclease GEN1, and a resolvase comprised of the SLX4-SLX1 and MUS81-EME1 nucleases. However, some chromatin bridges nevertheless remain, and the failure to process those would lead to chromosome breakages if not resolved before the completion of cytokinesis. The NoCut checkpoint detects chromatin bridges and delays the abscission of daughter cells to allow for more time to facilitate chromatin bridge resolution. However, very little is known about how chromatin bridges are eventually resolved and how this is coordinated with the NoCut checkpoint.
Taking advantage of advanced genetic and cell biological approaches in C. elegans, we recently uncovered a fundamentally new mechanism of how chromatin bridges are processed by the conserved LEM-3 nuclease right at the midbody, the structure where cells abscise just before cytokinesis is completed. We aim to investigate the mechanistic details of this pathway and how it is coordinated with cell cycle progression, both in C. elegans and in human cells. Studying such mechanisms is important for better understanding cancer progression. Late-stage tumor cells often polyploidize and have unstable karyotypes, a phenotype that occurs when DNA bridges are not processed by LEM-3. Alleles of the LEM-3 ortholog Ankle1 are associated with increased severity of breast and ovarian cancer.